Chad A. Witt

Acute Antibody-mediated Rejection After Lung Transplantation

BACKGROUND Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features. METHODS We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction. RESULTS We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days. CONCLUSIONS Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.

Implementation of a real-time computerized sepsis alert in nonintensive care unit patients*

Objective:Early therapy of sepsis involving fluid resuscitation and antibiotic administration has been shown to improve patient outcomes. A proactive tool to identify patients at risk for developing sepsis may decrease time to interventions and improve patient outcomes. The objective of this study was to evaluate whether the implementation of an automated sepsis screening and alert system facilitated early appropriate interventions. Design:Prospective, observational, pilot study. Setting:Six medicine wards in Barnes-Jewish Hospital, a 1250-bed academic medical center. Patients:Patients identified by the sepsis screen while admitted to a medicine ward were included in the study. A total of 300 consecutive patients were identified comprising the nonintervention group (n = 200) and the intervention group (n = 100). Interventions:A real-time sepsis alert was implemented for the intervention group, which notified the charge nurse on the patients hospital ward by text page. Measurements and Main Results:Within 12 hrs of the sepsis alert, interventions by the treating physicians were assessed, including new or escalated antibiotics, intravenous fluid administration, oxygen therapy, vasopressors, and diagnostic tests. After exclusion of patients without commitment to aggressive management, 181 patients in the nonintervention group and 89 patients in the intervention group were analyzed. Within 12 hrs of the sepsis alert, 70.8% of patients in the intervention group had received ≥1 intervention vs. 55.8% in the nonintervention group (p = .018). Antibiotic escalation, intravenous fluid administration, oxygen therapy, and diagnostic tests were all increased in the intervention group. This was a single-center, institution- and patient-specific algorithm. Conclusions:The sepsis alert developed at Barnes-Jewish Hospital was shown to increase early therapeutic and diagnostic interventions among nonintensive care unit patients at risk for sepsis.

Mechanisms of Remodeling in Asthmatic Airways

Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and reversible airflow obstruction. Subgroups of asthma patients develop airflow obstruction that is irreversible or only partially reversible and experience an accelerated rate of lung function decline. The structural changes in the airways of these patients are referred to as airway remodeling. All elements of the airway wall are involved, and remodeled airway wall thickness is substantially increased compared to normal control airways. Airway remodeling is thought to contribute to the subphenotypes of irreversible airflow obstruction and airway hyperresponsiveness, and it has been associated with increased disease severity. Reversal of remodeling is therefore of paramount therapeutic importance, and mechanisms responsible for airway remodeling are feasible therapeutic targets for asthma treatment. This paper will focus on our current understanding of the mechanisms of airway remodeling in asthma and potential targets for future intervention.

Pulmonary infections following lung transplantation.

Infectious complications are a major cause of morbidity and mortality in solid organ transplant recipients. Infections with viruses, bacteria, and fungi have all been associated with the development of bronchiolitis obliterans syndrome (chronic allograft rejection) in lung transplant recipients. Lung transplant recipients have a higher risk of infectious complications than recipients of other solid organs because of the intensity of immunosuppression, blunted cough mechanism, and constant exposure to the environment. This review provides a broad overview of the infectious complications encountered in caring for patients who have undergone lung transplantation.

Hyperammonemia Syndrome After Lung Transplantation: A Single Center Experience.

Background Hyperammonemia is a rare, often fatal complication after transplantation. The etiology is unknown, but recognition and rapid treatment may help to improve the survival of this unusual syndrome. We present the largest case series to date of hyperammonemia after lung transplantation (LTx) and discuss a treatment protocol that has been developed at our institution. Methods We conducted a retrospective cohort series of patients who underwent LTx between January 1, 2000, and December 31, 2013. Patients who developed hyperammonemia syndrome in the posttransplantation period, which was defined as symptoms of encephalopathy and plasma ammonia level exceeding 200 &mgr;mol/L on at least 1 occasion, were included. Data including demographics, antimicrobial and immunosuppression regimens, ammonia levels and other pertinent laboratory data, treatments administered, and outcomes were recorded. Results Eight of 807 lung transplant recipients developed hyperammonemia syndrome postoperatively during this time period. Median time to onset was 9.0 days, and median peak ammonia level was 370 &mgr;mol/L. All 8 patients were treated with hemodialysis, 7 of 8 patients were treated with bowel decontamination, and 5 of 8 patients were treated with nitrogen scavenging agents. Six of the 8 patients died. Conclusions The incidence of hyperammonemia syndrome in LTx patients was approximately 1%. Future research is needed to determine the efficacy of treatment, including hemodialysis, bowel decontamination, antibiotics, and the use of nitrogen scavenging agents in lung recipients with hyperammonemia.

The impact of pre-transplant allosensitization on outcomes after lung transplantation

BACKGROUND Allosensitization can be a significant barrier to transplantation for some patients, and previous studies suggested that pre-transplant allosensitization was associated with worse outcomes after lung transplantation. However, human leukocyte antigen (HLA) antibody testing has evolved significantly over the past 10 years, and current assays are highly sensitive and specific. METHODS We examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays in this retrospective, single-center study of 304 adult transplant recipients between January 1, 2006, and December 31, 2012. We accepted donor organs for allosensitized patients if a virtual crossmatch was compatible with all previously identified antibodies. RESULTS In univariate and multivariate Cox proportional hazards models, pre-transplant allosensitization, the calculated panel reactive antibody, and the number of pre-transplant HLA antibodies were not associated with the development of acute cellular rejection, lymphocytic bronchiolitis, donor-specific HLA antibodies, chronic lung allograft dysfunction, or graft failure. CONCLUSIONS Pre-transplant allosensitization does not adversely affect outcomes after lung transplantation when the potentially reactive HLAs are avoided in the donor by a virtual crossmatch with the recipient.

Immunosuppression: what's standard and what's new?

Lung transplantation is the ultimate treatment option for patients with end-stage lung disease. Chronic rejection, in the form of bronchiolitis obliterans syndrome, and noncytomegalovirus infections are the major causes of morbidity and mortality beyond the first year after transplantation. Most lung transplant recipients are treated lifelong with a three-drug immunosuppression regimen consisting of a calcineurin inhibitor, an antimetabolite, and low-dose corticosteroids. However, induction and maintenance immunosuppression strategies vary widely between centers, and a consensus on the ideal management of this patient population remains elusive. Over the past 20 years, several studies comparing the calcineurin inhibitors cyclosporine and tacrolimus and other studies comparing the antimetabolites azathioprine and mycophenolate mofetil have been performed. Additionally, the role of mammalian target of rapamycin (mTOR) inhibitors in the treatment of lung transplant recipients and the utility of azithromycin to treat and prevent bronchiolitis obliterans syndrome are areas of active investigation. This review discusses induction and traditional maintenance immunosuppressive agents and regimens and the evidence that exists to help guide therapy. Newer research involving the use of mTOR inhibitors in place of calcineurin inhibitors or antimetabolites and azithromycin for the treatment and prevention of bronchiolitis obliterans syndrome is also explored.

ISHLT Consensus ReportsPrimary Lung Graft DysfunctionReport of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading—A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation

From the Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia; Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Institute for Advanced Organ Disease and Transplantation, Tampa General Hospital/University of South Florida, Tampa, Florida; Department of Surgery, Michigan State University, Ada, Michigan; Lung Transplant Program, University of Chicago, Chicago, Illinois; Lung Transplant Program, Harefield Hospital, Harefield, United Kingdom; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida; Division of Pulmonary Medicine, Medical University of South Carolina, Charleston, South Carolina; Section of Lung Transplantation, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Section of Pulmonary and Critical Care, Department of Medicine, and Lung Transplant Program, University of Chicago, Chicago, Illinois; Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio; National Pulmonary Hypertension Service (Newcastle), The Newcastle upon Tyne Hospitals NHS Foundation Trust, and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

The Role of C4d Deposition in the Diagnosis of Antibody-Mediated Rejection after Lung Transplantation

Antibody‐mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single‐center study to characterize cases of C4d‐negative probable AMR and to compare these to cases of definite (C4d‐positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d‐positive and 45 (62%) were C4d‐negative. The two groups had a similar clinical presentation, and although more patients in the C4d‐positive group had neutrophilic capillaritis (54% vs. 29%, P = .035), there was no significant difference in the presence of other histologic findings. Despite aggressive antibody‐depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but that the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may respond initially to therapy, there is a high incidence of CLAD and poor survival after AMR.

Current perspectives on antibody-mediated rejection after lung transplantation

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Transplant Research and Risk Management 2014:6 109–115 Transplant Research and Risk Management Dovepress